The induction of mania in patients treated with antidepressants is a complex and not rare phenomenon, which has been described to occur with different frequencies in Bipolar Disorder (BP), Unipolar Disorder (UP), and Obsessive-Compulsive Disorder (OCD) (1–8). In Mood Disorder (MD) patients, the frequency of induction of mania during antidepressant treatment has been estimated to be 9.5–33%, varying in the different studies including different diagnoses (i.e. UP and BP) and different antidepressant treatments (9–11). More recently, it has become clearer that the phenomenon of antidepressant-induced mania is strictly related to a diagnosis of BP. In BP patients the switch rate during antidepressant treatment is definitively higher than in UP patients (12) and represents a critical issue for the long-term management of the disorder. Whether the type of antidepressant treatment can affect the risk of developing manic switches remains controversial. According to the report of Solomon et al (2), an antidepressant-induced manic episode occurs in approximately 20% of the inpatient admissions with a diagnosis of BP, independently from the treatment status (tricyclic antidepressants -TCAs-, monoamine oxidase inhibitors -MAOIs- or electroconvulsive therapy -ECT-). On the other hand, some studies have shown that the rate of induction of mania is higher in BP patients treated with TCAs and MAOIs than in BP patients treated with selective serotonin reuptake inhibitors (SSRIs) (8, 13).
As the impact on the natural course of BP and on the clinical management of the disease created by the occurrence of antidepressant-induced manic switches is quite high (1, 14), the detection of poss predictors of this phenomenon has become one of the primary goals of clinical studies. A higher number of previous manic or hypomanic episodes appeared to be the only clinical variable affecting the risk for developing induced mania during antidepressant treatment (8, 12). According to the report of Stoll et al. (15) antidepressant-induced manic/hypomanic episodes appear to be also clinically different from the spontaneous ones, usually having a shorter duration and less severe psychotic symptoms (15).
Most of the antidepressants commonly used to treat the depressive episodes that occur in the course of BP, act on the serotonin transporter (5HTT) (16). The 5HTT is located on the terminals of serotonergic neurons and its function is to reuptake serotonin from the synaptic cleft into the cell (16). Family, twin, and molecular genetic studies, have shown that BP has a strong genetic component (17–20), and thus, the 5HTT protein gene has been considered an good candidate for the investigation of the genetic component of both BP and the response to antidepressant medication.
The 5HTT gene is located on Chromosome 17, spans 31 kilobases (KB) and consists of 14 exons. This gene has two polymorphisms known. One is in the promoter region (5HTTLPR) consisting of 44 bp insertion/deletion (21). Studies employing lymphoblastoid cell lines containing different genotypes with respect to the 5-HTTLPR (21) showed that cells homozygous for the l allele produced steady-state concentrations of 5-HTT mRNA that were 1.4 to 1.7 times those in cells containing 1 or 2 copies of the s. At the protein level, membrane preparations from I/I lymphoblasts bound 30% to 40% more of a labeled marker than did membranes from I/s or s/s cells. Moreover, uptake of labeled serotonin in cells homozygous for the l allele of the promoter polymorphism was 1.9 to 2.2 times that in cells carrying 1 or 2 endogenous copies of the s variant. These data also suggested that the polymorphism has more of a dominant-recessive than a codominant-additive effect. in rare circumstances, particularly in Asian and African-American populations, additional variants such as the vl (very long) allele and the xl (extra long) allele may occur (22).
Investigation for the possible involvement of the 5HTTLPR in the pathogenesis of BP, applying different methods, has lead to conflicting results. Two linkage studies to date using multiplex families have provided negative results (23–24). Among the several case-control association studies performed, only two studies detected a positive association between the s variant of the gene and BP (25–26). Two studies applying strategies for the detection of association in presence of linkage disequilibrium, which are particularly useful for assessing gene susceptibility in psychiatric disorders where genes may be of small effect (27), gave negative results (28–29).
The other polymorphism known for the 5HTT gene is a variable number of tandem repeats (VNTR) polymorphism in the second intron, with three alleles (Stin2.9, Stin2.10 and Stin2.12) (30). The Stin2.12 allele was found to be associated with BP in two studies (25, 31), while more recent studies appear to exclude any associations between this polymorphism and BP (32–35).
At least three studies to date have considered the two known polymorphisms of the 5HTT gene in a haplotype analysis, with negative results (26, 35, 36).
With respect to the role of the 5HTTLPR in the antidepressant response, patients with Major Depression and homozygous or heterozygous for the l variant appear to show a better response to fluvoxamine (37) and paroxetine (38) and patients with Bipolar Depression who are homozygous for the l variant of the 5HTTLPR have been found to have a better clinical response to total sleep deprivation (39).
On the other hand, the meaning of these findings, as well as the relationships with the functional variations associated with the gene are controversial (40).